(12) United States Patent

Transcription

1 USOO B2 (12) United States Patent Li et al. (54) OSELTAMIVIR PHOSPHATEGRANULE AND PREPARATION METHOD THEREOF (75) Inventors: Song Li, Beijing (CN); Wu Zhong, Beijing (CN); Junhai Xiao, Beijing (CN); Yunde Xie, Beijing (CN); Xingzhou Li, Beijing (CN); Hao Cui, Beijing (CN); Zhibing Zheng, Beijing (CN) (73) Assignee: Institute of Pharmacology and Toxicology Academy of Military Medical Sciences P.L.A. China, Beijing (CN) (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under U.S.C. 4(b) by 709 days. (21) Appl. No.: 12/2,9 (22) PCT Filed: Aug. 11, 2006 (86). PCT No.: PCT/CN2OO6/OO2O43 S371 (c)(1), (2), (4) Date: Nov. 19, 2008 (87) PCT Pub. No.: WO2007/ PCT Pub. Date: Oct. 11, 2007 (65) Prior Publication Data US 2009/O A1 Jul. 9, 2009 () Foreign Application Priority Data Apr. 4, 2006 (CN) OO66995 (51) Int. Cl. A6 IK 9/14 ( ) A6 IK3I/ ( ) A6 IK 9/16 ( ) A61 K9/00 ( ) (52) U.S. Cl. CPC... A6 IK3I/2 ( ); A61 K9/141 ( ); A61 K9/0056 ( ); A61 K 9/0095 ( ); A61K 9/1623 ( ); A61 K9/16 ( ); A61 K9/1652 ( ) (58) Field of Classification Search None See application file for complete search history. (56) References Cited 5,607,697 A * 5,972,668 A 6,534,087 B2 7,074,431 B2 2002fOO18812 A1 U.S. PATENT DOCUMENTS 3/1997 Alkire et al /495 /1999 Georget al. 3/2003 Busson et al. 7/2006 Busson et al. 2, 2002 Busson et al. 2003, OO A1 2/2003 Busson et al. 2004/00628O1 A1* 4/2004 Faour et al / /O A1*, 2004 Alles et al ,651 () Patent No.: () Date of Patent: May 19, / A1 2009/ A1 20/ A1 6/2006 Busson et al. 7, 2009 Li et al. 9/20 Kubota et al. FOREIGN PATENT DOCUMENTS CN EP A A1 8, /2008 JP , 1998 JP , 2005 JP WO WO 2007/0973 A1 9, , 2007 OTHER PUBLICATIONS Oo et al., Pharmacokinetics and Dosage Recommendations for an Oseltamivir Oral Suspension for the Treatment of Influenza in Chil dren'. PaediatrDrugs, 2001, vol. 3., issue 3, pp * International Search Report, dated Jan. 11, 2007, corresponding to PCT/CN Notice of Allowance dated Nov. 12, 20, with partial English trans lation, for corresponding Chinese Patent Application No OO Office Action dated Jun. 11, 20, with partial English translation, for corresponding Chinese Patent Application No Office Action dated Sep. 4, 2009, with partial English translation, for corresponding Chinese Patent Application No Office Action datedmar. 1, 20, with partial English translation, for corresponding Chinese Patent Application No Examination Report dated Aug. 7, 2013 issued in corresponding European Patent Application No , 5pp. Extended European Search Report for corresponding EP Application No , dated Nov. 12, 2012, 6pp. Emea; Tamiflu: EPAR-Scientific Discussion': Tamiflu oseltamivir European public assessment report: Assessment history; Oct. 21, 2005, pp. Office action for corresponding Japanese Patent Application No , dated Apr. 17, 2012, 4pp. Tamiflu Dry Syrup 3%; Anti-influenza medicine; 3pp. Office action for corresponding Japanese Patent Application No , dated Sep. 4, Tamiflu; 2005; pp (Japanese Language). Japanese Language, 1994, pp , 0, , and 138. Japanese Language article, 1971, pp. -. * cited by examiner Primary Examiner Jeffrey S Lundgren Assistant Examiner Stephanie Springer (74) Attorney, Agent, or Firm Christie, Parker & Hale, LLP (57) ABSTRACT The present invention relates to an oseltamivir phosphate granule and preparation method thereof. The said granule comprises wt.% oseltamivir phosphate, wt.% diluent, wt.% binder, optionally wt.% edible flavoring essence, Sweetener and/or edible pigment. It is prepared by using - V/v% aqueous ethanol solution as moistening agent. The granules prepared by the formulation and method according to the present invention have good uniformity and stability and are water-soluble. The adminis tration dosage of the granules can be conveniently selected based on the age and body weight of patients. The oseltamivir phosphate granule is suitable for administering to old people, children and flu gravis patients and those patients that Swal low inconveniently or difficulty. The preparation of the gran ule is simple and low in production cost. 12 Claims, No Drawings

2 1. OSELTAMVR PHOSPHATE GRANULE AND PREPARATION METHOD THEREOF CROSS REFERENCE TO RELATED APPLICATION This application is National Phase Patent Application and claims the priority of International Application Number PCT/ CN2006/002043, filed on Aug. 11, 2006, which claims pri ority of Chinese Patent Application Number , filed on Apr. 4, TECHNICAL FIELD The present invention relates to oseltamivir phosphate granules and preparation method thereof. BACKGROUND ART Neuramidinase (NA) inhibitor is an anti-flu virus drug that has been developed recently. As a recently developed NA inhibitor, oseltamivir phosphate is effective to type A and B flu virus and has advantages of anti-drug fast, good tolerance of patient and high safety, and is used for the prevention and treatment of flu. is a therapeutic drug for preventing and controlling pandemic of flu used by World Health Organization and Chinese Ministry of Public Health, and also a drug reserved for national strategy to prevent and control pandemic of flu in China and other countries in the world. At present, commercial oseltamivir preparation form in China is capsule, its unit dose is 98.5 mg/granule (which contain oseltamivir 75 mg), according to body weight-dose table recommended to children over 1 year old, oseltamivir phosphate is taken in a dose as listed as follows: Body weight Recommended dose (taken for 5 days) s kg mg, twice per day >-23 kg mg, twice per day >23- kg 60 mg, twice per day > kg 75 mg, twice per day Clearly, due to large dose, the capsule cannot be exactly administered to Children patients especially lower age chil dren, and thereby the safety of administration cannot be guar anteed; on the other hand, since old people, children and flu gravis patients Swallow inconveniently or difficulty, capsule dosage form is not suitable for these special human. There fore, it is necessary to develop new dosage form of oselta mivir phosphate suitable for old people, children and flu gravis patients. SUMMARY OF THE INVENTION The inventor has developed oseltamivir phosphate gran ules having a plurality of advantages; for example, granules are water soluble, which can be taken after mixing with water, and thereby suitable for children and patients that are difficult to Swallow capsules. The administration dose can be conve niently selected according to the age and body weight of patients. Moreover, the preparation is simple and low cost. Hence, the present invention at one aspect relates to osel tamivir phosphate granules. Said granules comprise oselta mivir phosphate, at least one diluent, at least one binder and optionally edible flavouring essence, Sweetener and/or edible pigment Particularly, the oseltamivir phosphate granules according to the present invention comprise wt.% oseltamivir phosphate, wt.% diluent, wt.% binder, and optionally wt.% edible flavouring essence, Sweetener and/or edible pigment. The sum of various ingredients is equal to or less than 0%. The present invention at another aspect provides a method for the preparation of oseltamivir phosphate granules, which comprises the steps of mixing oseltamivir phosphate, diluent, binder and optionally edible flavoring essence, Sweetener and/or edible pigment, preparing soft material, passing through sieve, pelletizing, and finishing granules. According to one embodiment of the present invention, oseltamivir phosphate granules per gram comprise g oseltamivir phosphate, and diluent, binder and optionally edible flavoring essence, sweetener and/or edible pigment. According to another embodiment of the present invention, the oseltamivir phosphate granules of the present invention comprise: wt.% Diluent wt.% Binder wt.% Optionally wt.% edible flavouring essence, sweet ener and/or edible pigment. The Sum of the various ingredients is equal to or less than 0%. According to further embodiment of the present invention, oseltamivir phosphate granules per unit dose contain -1 mg of oseltamivir, as active ingredient, for example, per unit dose contains mg, mg. mg. mg, 60 mg, 75 mg or 90 mg of oseltamivir, preferably mg and mg of oselta mivir. The granules of the present invention are prepared into a soft material with - V/v%, preferably v/v % of ethanol aqueous solution as wetting agent. Therefore, the obtained granules have appropriate degree of tightness, good fluidity, exact package amount, uniform content, and high release degree. According to the present invention, the diluent used in oseltamivir phosphate granules is selected from one or two of powdered Sugar, dextrin, Sorbitol. Said powdered Sugar includes but is not limited, glucose, Aspartame, Steviosin, etc. Sugar in common sense; said diluent can simul taneously have action of modifying the taste; the binder is selected from one or more of carboxymethylcellulose Sodium, methylcellulose, povidone, tragacanth, acacia, the binder can have simultaneously Suspension promotion; the Sweetener is selected from, glucose, Aspartame or Steviosin. The more preferred formulations according to the present invention are demonstrated in Examples. The oseltamivir phosphate granules of the present inven tion are prepared by following steps: 1) drying oseltamivir phosphate, diluent and binder at -60 C. for 4 hours, crushing and passing through 0 mesh sieve; 2) exactly weighing oseltamivir phosphate, diluent and binder in formation amount, optically adding edible flavour ing essence, mixing uniformly by equivalent increase method to give a mixture powder; 3) preparing soft material with - V/v % ethanol aque ous solution, passing through 14 mesh sieve and pelletizing; 4) drying the wet granules at -60 C. completely, finish ing the granules by passing through 14 mesh sieve to give dried granules;

3 3 5) passing the dried granules through No. 5 sieve to remove fine powders, determining the content of the primary phar maceutical of the granules and moisture, defining package amount, packing; or mixing the dried granules and edible pigments uniformly and packing to give oseltamivir phos phate granules. The granules of the present invention are in the form of unit dose, they can be packed in a bottle or in a bag. Per bottle or bag contains g granules. Preferably, the formulation is packed using aluminum and plastic composite film, per bag contains g granules. It has been found by testing the obtained granules that the granules of the present invention (especially the granules prepared by the preferred formulation) have following advan tages: (1) appropriate degree of tightness, good fluidity, exact package amount, uniform content, and high release degree; (2) good stability of granules, long storage time; (3) the granules is water-soluble; the resultant aqueous Solution is clear and transparent and good taste; the children exhibits high compliableness to it, and meanwhile the bio availability of oseltamivir phosphate is enhanced; (4) the granules is convenient in administration, dissolves immediately in mouth, it can be taken by buccal or with water; (5) the production process is simple and low cost; (6) the determination of administration dose of children's patients is easy. EMBODIMENTS Example 1 Preparation of Oseltamivir Phosphate Granules in Powidone k 19.7 g (containing g of Oseltamivir) g 12 g 600 g and adjuvants were crushed to pass through 0 mesh sieve. oseltamivir phosphate, povidone k and were weighed exactly in an amount in the formulation, and mixed uniformly by equivalent increase method; the mixture was prepared into a soft material with V/v '% ethanol aqueous Solution, passed through 14 mesh sieve and pelletized. The wet granules were dried at -60 C. in an oven, finished by passing through 14 mesh sieve, Sieved using No. 5 sieve to remove fine powder. The content of the primary drug of the granules and moisture were determined, and the package amount was determined. The obtained gran ules were packed with aluminum plastic composite film into packages of 0.6 g/per unit dose, which contains mg of containing mg or mg of Example 2 Preparation of Oseltamivir Phosphate Granules in Powidone k 19.7 g (containing g of Oseltamivir) g 12 g 00 g and adjuvants were crushed to pass through 0 mesh sieve. oseltamivir phosphate, povidone k and were weighed exactly in an amount in the formulation, and mixed uniformly by equivalent increase method; the mixture was prepared into a soft material with V/v '% ethanol aqueous Solution, passed through 14 mesh sieve and pelletized. The wet granules were dried at -60 C. in an oven, finished by passing through 14 mesh sieve, Sieved using No. 5 sieve to remove fine powder. The content of the primary drug of the granules and moisture were determined, and the package amount was determined. The obtained gran ules were packed with aluminum plastic composite film into packages of 1.0 g/per unit dose, which contains mg of containing mg or mg of Example g (containing g of Oseltamivir) g 20 g 00 g containing mg, mg or mg of Example g (containing g of Oseltamivir)

4 5 -continued g. 24 g 1200 g composite film into packages of 1.2 g/per unit dose, which containing mg, mg or mg of Example g (containing g of Oseltamivir) g 36 g 1800 g containing mg, mg, mg, 60 mg or 75 mg of oselta mivir. Example 6 2O 78.8 g. (containing 60 g of Oseltamivir) g g 65 6 containing mg, mg, mg, 60 mg, 75 mg or 90 mg of Example g (containing 75 g of Oseltamivir) g 60 g 00 g containing mg, mg, mg, 60 mg, 75 mg, 90 mg or 1 mg of Example 8 ng Specification g (containing 1 g of Oseltamivir) g. 120 g 6000 g containing mg, mg, mg, 60 mg, 75 mg, 90 mg or 1 mg of Example 9 Preparation of Oseltamivir Phosphate Granules in Carboxymethylcellulose sodium g (containing g of Oseltamivir) g 00 g and adjuvants were crushed to pass through 0 mesh sieve., carboxym

5 7 ethylcellulose Sodium and were weighed exactly in an amount in the formulation, and mixed uniformly by equivalent increase method; the mixture was prepared into a Soft material with % ethanol aqueous solution, passed through 14 mesh sieve and pelletized. The wet granules were dried at -60 C. in an oven, finished by passing through 14 mesh sieve, sieved using No. 5 sieve to remove fine powder. The content of the primary drug of the granules and moisture were determined, and the package amount was determined. composite film into packages of 1.0 g/per unit dose, which containing mg, mg, mg, mg or 75 mg of oselta mivir. Example Methylcellulose sodium g (containing g of Oseltamivir) g 20 g 00 g and adjuvants were crushed to pass through 0 mesh sieve. oseltamivir phosphate, methylcellu lose sodium and were weighed exactly in an amount in the formulation, and mixed uniformly by equivalent increase method; the mixture was prepared into a soft mate rial with V/v '% ethanol aqueous solution, passed through 14 mesh sieve and pelletized. The wet granules were dried at -60 C. in an oven, finished by passing through 14 mesh sieve, sieved using No. 5 sieve to remove fine powder. The content of the primary drug of the granules and moisture were determined, and the package amount was determined. The obtained granules were packed with aluminum plastic com posite film into packages of 1.0 g/per unit dose, which con tains mg of containing mg, mg, mg, mg or 75 mg of oselta mivir. Example 11 Preparation of Oseltamivir Phosphate Granules in g (containing 1 g of Oseltamivir) g g 00 g contains 1 mg of containing mg. mg, mg, 60 mg, 75 mg, or 90 mg of Example 12 Test of Solubility and Dispersibility of Oseltamivir Phosphate When the granules obtained in Example 1 were prepared with water into a solution containing 5 mg/ml of oseltamivir, the ph was tested to be about 5.4, the solution was neutral to weakly acid solution, had no stimulus to human body, had good taste, and was in favor of use of patients. According to the requirements of Chinese Pharmacopoeia, 2005 edition, Part 2, Annex IX B, the second method (double sieving method), the sum of No. 1 oversize product and No. 5 undersize product should not exceed % of test samples. The test results showed that aforesaid granules samples were all in conformity with the requirements of Chinese Pharma copoeia to completely guarantee the uniformity of the particle size of the granules, so that the quality of the granules was not influenced by damp caking or breaking during transportation and storage. g of said granules samples was added with 200 ml of hot water, stirred for 5 min, the solubility of the samples was observed. The test results showed that the samples dissolved completely, no foreign matters appeared, in conformity with the requirements of Chinese Pharmacopoeia, 2005 edition, Part 2, Annex IN. The prepared soluble oseltamivir phosphate granules can completely disperse or dissolve in water, so as to ensure the bioavailability of the granules and be convenient for the use of patients. What is claimed is: 1. granules, comprising: at SucroSeat povidone k at 3.28 wt.%; wt.%; and 2.OO wt.%. 2. The oseltamivir phosphate granules of claim 1, wherein per unit dose the oseltamivir phosphate granules contain mg or mg of 3. A method for preparing the oseltamivir phosphate gran ules of claim 1, comprising: drying the oseltamivir phosphate, the, and the povidone k at -60 C. for 4 hours to form dried components; crushing the dried components through a 0 mesh sieve; exactly weighing the oseltamivir phosphate, the, and the povidone k informulation amount, optionally adding an edible flavoring essence; mixture powder; adding - V/v % of ethanol aqueous solution to the

6 determining package amount, packing or mixing the dried prepare the oseltamivir phosphate granules. 4. granules, comprising: at at povidone k at 1.97 wt.%; wt.%; and 1.2O wt.%. 5. The oseltamivir phosphate granules of claim 4, wherein per unit dose the oseltamivir phosphate granules contain mg or mg of 6. A method for preparing the oseltamivir phosphate gran ules of claim 4, comprising: drying the oseltamivir phosphate, the, and the povidone k at -60 C. for 4 hours to form dried components; crushing the dried components through a 0 mesh sieve; exactly weighing the oseltamivir phosphate, the, and the povidone k informulation amount, optionally adding an edible flavoring essence; mixture powder, adding - V/v % of ethanol aqueous solution to the determining package amount, packing or mixing the dried prepare the oseltamivir phosphate granules. 7. granules, comprising: at SucroSeat carboxymethylcellulose sodium at 3.28 wt.%; wt.%; and 2.OO wt.%. 8. The oseltamivir phosphate granules of claim 7, wherein per unit dose the oseltamivir phosphate granules contain mg or mg of 9. A method for preparing the oseltamivir phosphate gran ules of claim 7, comprising: drying the oseltamivir phosphate, the, and the car boxymethylcellulose sodium at -60 C. for 4 hours to form dried components; crushing the dried components through a 0 mesh sieve; exactly weighing the oseltamivir phosphate, the, and the carboxymethylcellulose sodium in formulation amount, optionally adding an edible flavoring essence; mixture powder; adding - V/v % of ethanol aqueous solution to the determining package amount, packing or mixing the dried provide the oseltamivir phosphate granules.. granules, comprising: at SucroSeat methylcellulose sodium at 3.28 wt.%; wt.%; and 2.OO wt.%. 11. The oseltamivir phosphate granules of claim, wherein per unit dose the oseltamivir phosphate granules contain mg or mg of 12. A method for preparing the oseltamivir phosphate gran ules of claim, comprising: drying the oseltamivir phosphate, the, and the methylcellulose sodium at -60 C. for 4 hours to form dried components; crushing the dried components through a 0 mesh sieve; exactly weighing the oseltamivir phosphate, the, and the methylcellulose sodium in formulation amount, optionally adding an edible flavoring essence; mixture powder; adding - V/v % of ethanol aqueous solution to the determining package amount, packing or mixing the dried prepare the oseltamivir phosphate granules. k k k k k